We propose to study epigenetic changes in normal breast epithelial cells responding to physiological stimulation and environmentally perturbation. Integrative omic approaches will be used to determine global chromatin profiles in estrogen receptor (ER)1-positive cells stimulated with ligands. Complex regulatory networks of ER1 signaling are activated with concomitant alterations of chromatin in responsive genes. The expression of these genes then returns to the basal level. Chromatin is in a semi-open state, poised to receive transcription factors or repressors when signaling is activated by the next cycle of ligand. The homeostasis of chromatin dynamics is perturbed when epithelial progenitor cells are continually exposed to estrogenic plasticizers like bisphenol A (BPA). We hypothesize that a subset of responsive genes is reprogrammed to undergo permanent silencing. Step-wise acquisition of repressive histone marks, polycomb repressors, and DNA methyltransferases may take place in these genes. This injury information can be heritably transmitted to the differentiated progeny, and DNA methylation is progressively accumulated in target CpG islands. Epigenomic mapping of these CpG islands may identify potential biomarkers that are used as environmental sensors for monitoring human exposures to environmental estrogens. Public Health Relevance: It remains to be conclusively determined if exposure to low-dose bisphenol A (BPA), an estrogenic plasticizer, is harmful to human health. The purpose of this study is to show that epithelial progenitors in the human breast are sensitive to BPA exposure. This injury memory is maintained by an epigenetic mechanism, leading to aberrant proliferation of differentiated progeny and increased risk of breast neoplasm. The cytology assay developed in the proposed study can be used to screen environmental agents for potential estrogenic effects in human cells. Furthermore, the identified epigenetic markers may be used to identify breast cancer patients with a prior history of exposure to BPA or other environmental estrogens. It is our hope that the result of this study supports an inclusion of the epigenetic effects of estrogenic plasticizers, like BPA, into risk assessment implemented by regulatory agencies.